5/24/2017

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Rich Rohaley, PharmD, RPh

Objectives� Describe the steroid hormone cascade

� Understand the pathophysiology of symptoms resulting

from hormone depletion

� Discuss menopausal treatment options including bio-

identical hormone replacement

� Apply laboratory results to guide hormone replacement

therapy dose adjustment

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E1→ ←E2

↑

E3

E1→~10%

←E2~10%

↑

E3 ~80%

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Lab ValuesFemale Male

� Estradiol

� Estrone

� FSH

� Progesterone

� LH

� Testosterone (total)

� DHEA-sulfate

� Cortisol

� Testosterone (free)

� Testosterone (total)

� Dehydrotestosterone

� DHEA-sulfate

� Estrogens (total)

� Progesterone

� Cortisol

Treatment Options

Treatment Options� Estrogens

� Premarin

� Cenestin & Enjuvia

� Estrace, Climara, Vivelle, Estring

� Femring

� Vagifem

� Estinyl

� Ortho-Est & Ogen

� Progesterone & Progestins

� Provera

� Prometrium

� Micronor & Aygestin

� Combinations

� Prempro

� Femhrt

� Activella & Combipatch

� Estratest

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Why patients ask for Bio-Identical� ‘Cause Oprah said so

� ‘Cause Suzanne Somers wrote that book

� They want to avoid pharmaceuticals

� To be more “natural”

What does Bio-Identical mean?� Hormone chemically identical to what the organ (ovary)

releases

� Further defined to come from a natural source

� Further defined as varying in concentration/strength;

designed to be specific for any one individual

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Why not just use commercial?� The only estradiol on the market today is derived from

the oil of the soy plant (tablets, patches, creams)

� Can help manage hot flashes

� At least it’s natural

� Chemically identical?

� Adjusted to be specific on per-patient basis?

� Premarin (Pre-Mare-in)

� Pregnant Mare’s (horse) Urine

� Study: Women’s Health Initiative (1991-2010)

� Long term risk of heart disease, breast cancer & more…

←

Birth Control

←

Horse Estrogen

Hormone Replacement Therapy

(HRT)� Much bad press about the dangers of hormone

replacement

� Max duration of treatment?

� Causes cancer?

� Harmful?

� “We don’t have to be rocket scientists, we just have to

copy nature” –Jonathan V. Wright

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Women’s Health InitiativeCompared with the placebo, estrogen plus progestin resulted in:

Compared with the placebo, estrogen alone resulted in:

� Increased risk of heart attack

� Increased risk of stroke

� Increased risk of blood clots

� Increased risk of breast cancer

� Reduced risk of colorectal cancer

� Fewer fractures

(study included only women 65 and

older)

� No difference in risk for heart attack

� Increased risk of stroke

� Increased risk of blood clots

� Uncertain effect for breast cancer

� No difference in risk for colorectal cancer

� Reduced risk of fracture

(Findings about memory and cognitive function are not yet available)

Progesterone and Anticancer

Studies� Simon JA, Robinson DE, Andrews MC, et al. The

absorption of oral micronized progesterone: The effect of

food, dose proportionality, and comparison with

intramuscular progesterone. Fertil Steril 1993;60:26-33.

� Kim S, Korhonen M, Wilborn W, et al. Antiproliferative

effects of low-dose micronized progesterone. Fertil Steril

1996;65:323-331.

E1→~10%

←E2~10%

↑

E3 ~80%

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Estrogens� Estradiol (E2) ~ 10-20% of circulating estrogen

� High potency

� Estrone (E1) ~ 10-20% of circulating estrogen

� Medium potency

� Estriol (E3) ~ 60-80% of circulating estrogen

� Low potency (1/100th the strength of E2)

� If it’s so weak, why bother with it?

Estriol (E3)� Originally (~90 years ago) thought to be just a metabolite

of estradiol

� “It would be unusual if nature produced three estrogens of which only one was utilized” –J.Wright

� E1 and E2 are competitively inhibited by E3

� This reduces estrogenicity/estrogen dominance

� Risk of cancer virtually vanishes

� Even in high doses does not promote endometrial proliferation

� Great treatment for vaginal atrophy (vaginal thinning or painful intercourse), recurrent UTI’s, incontinence

Estrogen in Bio-HRT� “TriEst”

� 10% : 10% : 80% (E1:E2:E3)

� 3 : 7 : 90

� Bi-Est

� Comprised of E2 and E3

� E1 removed due to potential side effects

� 10 : 90

� 20 : 80

� 50 : 50

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Estrogens� Estrogens increase HDL

� May be why premenopausal women are protected from

heart disease

� Maintain bone density

� Bisphosphonates maintain and may increase bone density

by 2-3%

� Combination HRT may increase bone density by >15%

Serum E2� Menopause = E2 <50pg/ml

� Associated with anxiousness & depression

� Postmenopausal women are found to feel the best when

E2 levels are between 50-150pg/ml

Progestins vs. Progesterone� Progestins:

� Synthetic “estrogens”

� Patentable receptor substitutes

� Ex: Provera®, Micronor®

� Progesterone

� Chemically identical

� Does not interfere with estrogen’s cardio-protection

� Virtually no unwanted effects

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Progesterone Intro� Important component of HRT

� Menopausal women with an intact uterus continue to

produce estrogen, and unopposed estrogen can further

stimulate the endometrial tissue

� Abnormal bleeding

� Endometrial cancer proliferation

� Must be added to estrogen therapy to reduce this

overstimulation

� Proven to reduce risk of endometrial cancer

Progesterone in HRT� Progesterone deficiency (w/relation to estrogen) may lead to:

� Swollen breasts / breast tenderness

� Headaches

� Low libido

� Depression / anxiety

� Mood swings / irritability

� Insomnia

� Lack of focus

� Acne

� Weight gain / bloating

� Joint pain

� Early menstruation

� Cramps

PMS & Pre or Peri-Menopause� Associated with declining estrogen, testosterone, and

progesterone

� Often the symptoms are misdiagnosed and treated as

individual symptoms

� Ex: Depression → SSRI’s (Prozac)

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HRT & Osteoporosis

HRT & Osteoporosis� Progesterone

� Can rebuild bone, even after it’s been lost

� Osteoblast activation

� DHEA

� Testosterone

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HRT & Menopause

Testosterone� Required to maintain:

� Skin tone

� Muscle mass & strength

� Can help with metabolism (muscle burns fat)

� Bone density

� Libido

� No accurate lab draw / no standard of measurement

� Too many non-hormonal factors

� We do know that testosterone increases desire

Testosterone Symptoms� Decreased testosterone in women:

� Lack of energy

� Decreased well-being

� Decreased bone mass

� Decreased libido

� Impaired sexual function

� Normal range for pre-menopausal women:

20 – 80 ng/ml

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Dosage Forms for HRT� Oral

� Capsules

� Buccal

� Troche

� Transdermal

� Creams

� Gels

� Vaginal

� Suppositories

� Creams

Patient Cases� LG is a 52 YOF with complaints of hot flashes and night

sweats that are waking her every two hours. She also

complains of fatigue and a mental “fog” affecting her

productivity at work

� What lab values could be useful?

� Is she a Bio-HRT candidate?

� Which hormones should be included?

Useful Lab ValuesFemale

� Estradiol

� Estrone

� FSH

� Progesterone

� LH

� Testosterone (total)

� DHEA-sulfate

� Cortisol

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Potential Starting Dose� Oral Capsule:

� TriEst (10/10/80%) 1mg

Progesterone 100mg

DHEA 5mg SR Capsule

� Take one capsule once daily for 10 days, then increase to

one capsule twice daily

Patient Cases� After initiating a sustained release capsule of TriEst 1mg

/Progesterone 100mg / DHEA 5mg four weeks ago, the

patient calls back complaining of mastalgia. Her hot

flashes are gone and she’s sleeping great. For this reason,

she’s willing to tolerate the tenderness. What should we

do?

Adjusted Dose

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Patient Cases� NH is a 42 YOF presenting with

weight gain and difficulty sleeping. She is a yoga instructor and exercises very regularly claiming nothing in her diet has significantly changed. She asks if there’s anything she can do for her weight that isn’t a “pharmaceutically engineered monster”.

� Labs

� E2 = 122 pg/ml

� E1 = 55 pg/ml

� FSH = 45 mIU/ml

� Progesterone = 0.2 ng/ml

� LH = 27 mIU/ml

� Cortisol = 4.7ug/dl

Potential Starting Dose� Transdermal Cream:

� Progesterone 100mg/ml Cream

� Apply 0.5ml to an area of thin skin every evening, rub in well and

rotate sites

Patient Cases� NH saw weight loss of 3 lbs

over 6 weeks. She decided that

if a little helped a little, a lot

may help a lot. She self

adjusted her dose to 2ml of the

cream. She now notes

regaining the lost weight with

10 extra lbs from baseline,

noting water retention and

bloating.

� Labs

� E2 = 116 pg/ml

� E1 = 56 pg/ml

� FSH = 43 mIU/ml

� Progersterone =

12 ng/ml

� LH = 2 mIU/ml

� Cortisol = 34 ug/dl

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Patient Cases� SP is a 49 YOF 6 years post hysterectomy. She has been on

0.05mg/24h Vivelle patch since the surgery. She’s

complaining of vaginal irritation and dryness leading to

uncomfortable intercourse and difficulty reaching climax.

She also notes that the mood never strikes like it used to.

� What labs would we look at?

� Options for dryness?

� Options for libido?

Options for SP� Dryness & Atrophy

� Estradiol 0.01%

Estriol 1% Vaginal Cream

� Apply a pea sized amount once daily for a week, then reduce to two days per week as needed for irritation.

� Libido

� Testosterone 1% Cream

� Apply 0.25ml to area of thin skin once each morning

� “Cuddle Cream”

� Testosterone 5% Ointment

� Apply a small amount to the clitoral area upon initiation of sexual activity

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Where to Get More Information� Pam W. Smith, MD

� Jonathan V. Wright, MD

Where to Get More Information

Conclusion� Hormones are highly interdependent and converted by

the aromatase enzyme family

� Pituitary hormones signal recruitment of hormones from

various body tissues when primary source is depleted,

leading to a variety of symptoms

� Bio-identical hormones are one of the many options for

treating menopause

� Laboratory results when combined with subjective

information, can help tailor medications to a safe and

efficacious dose

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Questions?